Even though there are many candidates in the wings to succeed BZs, the only major items that have reached the market are buspirone (Buspar) and selective serotonin reuptake inhibitors (SSRIs) such as paroxetine (Paxil), which have distinct profiles of action (Eison and Temple, 1986; Goddard et al., 1999). The therapeutic effect of these agents appears to be based on the ability of the serotonin [5-hydroxytryptamine (5-HT)] systems to modulate anxiety (Handley, 1995). Buspirone has the relatively selective effect of stimulating 5-HT1A receptors, which are concentrated on serotonin cell bodies. At this site, buspirone reduces serotonin neuronal activity, and hence it acutely diminishes serotonin release in higher brain areas, which can lead to long-term up-regulation of postsynaptic serotonin receptors.
Although some investigators believe that buspirone alleviates anxiety by reducing 5-HT activity, the benefits may also be due to a compensatory functional elevation of brain serotonin activity. There are abundant postsynaptic 5-HT1A receptors in the brain, and it presently remains possible that the postsynaptic effects of buspirone contribute as much to the antianxiety effects of this drug as binding to presynaptic sites. Thus, even though certain types of serotonin activity are anxiogenic [e.g., at the 5-HT2 site (Charney et al., 1987)], the antianxiety effects of buspirone may largely be due to a long-term postsynaptic facilitation of serotonin sensitivity in the brain (Stahl et al., 1992). Indeed, SSRIs such as venlafaxine (Effexor) may facilitate buspirone effects (Davidson et al., 1999; Sramek et al., 2002).
In any event, the therapeutic benefits of buspirone tend to be milder than those obtained with BZs, but fewer side effects are encountered. Buspirone produces no sedation, nor does it have any problematic short-term psychological effects that might promote abuse. It produces no dependence or withdrawal upon discontinuation. It also has no abuse potential. Unfortunately, buspirone appears to exhibit comparatively little benefit in those individuals who have previously benefited from BZs (Schweizer et al., 1986), perhaps because patients have become dependent on the strong, rapid, and easily perceived psychological changes produced by BZs. Accordingly, current practice is that buspirone should be the initial treatment of choice at the onset of long-term pharmacotherapy, while BZs are used more in short-term situations because of the possibility of dependence. Unlike some of the newer BZs such as alprazolam, buspirone has no efficacy as an antipanic agent.
It has long been recognized by clinicians that many antidepressants, especially the SSRIs, often rapidly ameliorate anxiety symptoms. After all, telencephalic serotonin systems inhibit practically all emotional and motivational processes within the brain. One SSRI, namely paroxetine (Paxil), is currently approved for the treatment of generalized anxiety disorders (Rocca et al., 1997) and others, especially extended-release venlaflaxine, are bound to follow (Davidson, 2001; Gorman, 2002). This does not mean that many of the other SSRIs would not be equally useful. They simply have not undergone the necessary clinical evaluations to receive approval. Most of the older tricyclic antidepressants had some anxiolytic effects (Rickels et al., 1993). There is not sufficient comparative clinical research to specify the differences in the profile of SSRI and tricyclic actions on anxiety as compared to the BZs. One straightforward possibility is that SSRIs are more effective for anxiety feelings commonly associated with depression. It has long been known that anxiety symptoms are often present in depression (Bakish, 1999). Of course, unlike the BZs and buspirone, the SSRI antianxiety agents have the added benefit of often counteracting depressive symptoms (Ninan, 1999).
Drugs are also available for managing the undesired peripheral physiological symptoms of anxiety. Palpitations and sweating can be reduced with 6-noradrenergic blockers (e.g., propranolol). Such "beta-blockers" effectively control the outward symptoms of anxiety such as those that commonly accompany public speaking and musical performances. Within the brain, it is also clear that 6-noradrenergic synapses promote the consolidation of fear memories (Cahill and McGaugh, 1998).
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